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Background & Aims: Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). However, biomarkers that predict treatment success and survival remain an unmet need., Methods: Patients with HCC put on PD-(L)1-based immunotherapy were included in a training set (n = 190; 6 European centers) and a validation set (n = 102; 8 European centers). We investigated the prognostic value of baseline variables on overall survival using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patients treated with sorafenib (n = 204)., Results: Baseline serum alpha-fetoprotein ≥100 ng/ml (hazard ratio [HR] 1.7; p = 0.007) and C-reactive protein ≥1 mg/dl (HR, 1.7; p = 0.007) were identified as independent prognostic factors in multivariable analysis and were used to develop the CRAFITY score. Patients who fulfilled no criterion (0 points; CRAFITY-low) had the longest median overall survival (27.6 (95% CI 19.5-35.8) months), followed by those fulfilling 1 criterion (1 point; CRAFITY-intermediate; 11.3 (95% CI 8.0-14.6) months), and patients meeting both criteria (2 points; CRAFITY-high; 6.4 (95% CI 4.8-8.1) months; p <0.001). Additionally, best radiological response (complete response/partial response/stable disease/progressive disease) was significantly better in patients with lower CRAFITY score (CRAFITY-low: 9%/20%/52%/20% vs. CRAFITY-intermediate: 3%/25%/36%/36% vs. CRAFITY-high: 2%/15%/22%/61%; p = 0.003). These results were confirmed in the independent validation set and in different subgroups, including Child-Pugh A and B, performance status 0 and ≥1, and first-line and later lines. In the sorafenib cohort, CRAFITY was associated with survival, but not radiological response., Conclusions: The CRAFITY score is associated with survival and radiological response in patients receiving PD-(L)1 immunotherapy. The score may help with patient counseling but requires prospective validation., Lay Summary: The immunotherapy-based regimen of atezolizumab plus bevacizumab represents the new standard of care in systemic first-line therapy of hepatocellular carcinoma (HCC). Biomarkers to predict treatment outcome are an unmet need in patients undergoing immunotherapy for HCC. We developed and externally validated a score that predicts outcome in patients with HCC undergoing immunotherapy with immune checkpoint blockers., Competing Interests: Conflict of interest B.S. received travel support from AbbVie, Ipsen and Gilead. K.P. nothing to disclose. M.K. received honoraria from BMS and AstraZeneca as consultant and is an investigator for AstraZeneca. F.H. received travel support from Bayer, Abbvie, and Gilead. F.F. received travel support from Abbvie and Novartis, and speaker fees from Abbvie and MSD. O.W. served as consultant for Amgen, Bayer, BMS, Celgene, Eisai, Merck, Novartis, Roche, Servier, and Shire. He served as a speaker for Abbvie, Bayer, BMS, Celgene, Falk, Ipsen, Novartis, Roche, and Shire. He received travel support from Abbvie, BMS, Ipsen, Novartis, and Servier. V.H. has nothing to disclose. K.S. Served as consultant for Ipsen and Bayer, and conducts studies for Bayer, Roche, Lilly, MSD, and BMS. J.v.F. has received advisory board fees from Roche. T.W.F. has nothing to disclose. M.S. has nothing to disclose. H.H. received compensations as a member of a scientific advisory board of Lilly. K.S. has nothing to disclose. S.S. has nothing to disclose. P.R. has nothing to disclose. A.R.S. has served at advisory boards and received consulting honoraria from AMGEN, AAA, Bayer, BMS, IPSEN, Lilly, Merck, MSD, Pfizer, Roche, Sanofi, and Servier. J.C.M. has received consulting honoraria from Abbvie, Astra Zeneca, Bayer, BMS, Eisai, Gilead, Incyte, Intercept, MSD, Sanofi, Vifor for work performed outside the current study. N.N.R. has nothing to disclose. F.K. received speakers' fees from Bayer, Ipsen, MSD, Eisai, Shire, Sirtex and has received travel grants from Eisai, Janssen, Ipsen and Novartis. D.T.W. served as speaker/expert testimony for AstraZeneca, Eisai, BMS, Celgene, Incyte, Ipsen, Falk, Novartis, Roche Pharma AG, Servier, Shire Baxelta, and Sirtex; he received travel support from Bayer Health Pharma, Celgene, Ipsen, Novartis, and SIRTEX, and research grants/funding from Servier. M.P.E. received consulting honoraria from BMS and MSD. A.T. received consulting honoraria and /or lecture fees from Bayer, IPSEN, Lilly, BMS, Eisai Novartis, Roche, Intercept, Falk, AbbVie, and Gilead. He received and travel grants from IPSEN, AbbVie, and Gilead. He is an investigator for IPSEN and GILEAD. S.D.D. received consulting honoraria from Amgen, Bayer, BMS, IPSEN, Lilly, Merck, BMS, Novartis, Pfizer, Roche, Sanofi, and Servier, and travel grants from Amgen, BMS, IPSEN, Roche, and Servier. D.J.P. received lecture fees from ViiV Healthcare, Bayer Healthcare, Falk, BMS, EISAI and Roche; travel expenses from BMS, MSD and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, H3B, Roche, Astra Zeneca, and DaVolterra; research funding (to institution) from MSD, BMS. T.P. received consulting fees from IQVIA and Bayer; and institutional research funding from Lilly, Roche, Bayer. T.M. has nothing to disclose. L.B. has nothing to disclose. C.M. has nothing to disclose. M.M. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol-Myers Squibb, Collective Acumen, Gilead, and W. L. Gore & Associates and received travel support from AbbVie, Bristol-Myers Squibb, and Gilead. T.R. received speaker fees from Boehringer Ingelheim, Roche, W.L. Gore and MSD, grant support from Boehringer Ingelheim, Boston Scientific, Cook Medical, Gilead, Guerbet, Abbvie, Phenex Pharmaceuticals, Philips, W.L. Gore, and MSD, served as a consultant for Abbvie, Bayer, Boehringer Ingelheim, Gilead, Intercept and MSD and received travel support from Gilead, Roche, MSD, and Gore. M.T. received speaker fees from Bristol-Myers Squibb (BMS), Falk Foundation, Gilead, Intercept and Merck Sharp & Dohme (MSD); advisory board fees from Abbvie, Albireo, Boehringer Ingelheim, BiomX, Falk Pharma GmbH, GENFIT, Gilead, Intercept, Janssen, MSD, Novartis, Phenex, Regulus and Shire; travel grants from AbbVie, Falk, Gilead, and Intercept; and research grants from Albireo, CymaBay, Falk, Gilead, Intercept, MSD, and Takeda. He is also coinventor of patents on the medical use of norUDCA filed by the Medical University of Graz. N.P. received consulting fees from Amgen, Merck Serono, Servier; lectures fees from AbbVie, Gilead, Lilly; travel fees from Amgen, ArQule; and institutional research funding from Basilea, Merck Serono, Servier. L.R. has received consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Zymeworks; lectures fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi; travel expenses from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks. M.B. received compensations as a member of scientific advisory boards of Bayer, Bristol–Meyers Squibb, EISAI, IPSEN, and MSD. J.T. served as consultant for Amgen, Bayer, BMS, Eisai, Lilly, Merck Serono, MSD, Ipsen, and Roche, received travel support from BMS and Ipsen, and speaking fees from Amgen, Bayer, BMS, Eisai, Lilly, Merck Serono, MSD, Ipsen, and Roche. He is also an investigator for Amgen, Bayer, BMS, Eisai, Lilly, Merck Serono, MSD, Ipsen, and Roche. A.W. received compensations as a member of scientific advisory boards for BMS, Wako, Sanofi and. He served as a speaker for Leo Pharma, Eisai, Ipsen and Roche and received travel support from Merck and Servier. H.W. served as speaker for Bayer, Eisai, Ipsen, and Roche, and as a consultant for Bayer, Eisai, Lilly, BMS, Roche, and Ipsen. He conducts studies for Bayer, Roche, Lilly, MSD, and BMS. J.F.D. received compensations as a member of scientific advisory boards of Abbvie, Bayer, Bristol-Myers Squibb, Falk, Galapagos, Genfit, Genkyotex, Gilead Sciences, HepaRegenix, Intercept, Lilly, Merck, and Novartis. M.P.R. is advisor/consultant for Astra Zeneca, Bayer, BMS, Eisai, Ipsen, Lilly, MSD, and Roche; he served as a speaker for Bayer, Eisai, Ipsen, Lilly, and Roche; he is an investigator for Bayer, BMS, Eisai, Exelixis, Lilly, and Roche. A.V. served as consultant for Roche, Bayer, Lilly, BMS, Eisai, and Ipsen, and received speaking fees form Roche, Bayer, Lilly, BMS, Eisai, and Ipsen. He is also an investigator for Roche, Bayer, Lilly, BMS, Eisai, and Ipsen. M.P. is an investigator for Bayer, BMS, Lilly, and Roche, he received speaker honoraria from Bayer, BMS, Eisai, and MSD, he is a consultant for Bayer, BMS, Ipsen, Eisai, Lilly, Roche, and MSD, and he received travel support from Bayer, BMS, and Roche. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Chronic viral hepatitis is associated with substantial morbidity and mortality worldwide. The aim of our study was to assess the ability of point shear-wave elastography (pSWE) using acoustic radiation force impulse imaging for the prediction of the following liver-related events (LREs): new diagnosis of HCC, liver transplantation, or liver-related death (hepatic decompensation was not included as an LRE). pSWE was performed at study inclusion and compared with liver histology, transient elastography (TE), and serologic biomarkers (aspartate aminotransferase to platelet ratio index, Fibrosis-4, FibroTest). The performance of pSWE and TE to predict LREs was assessed by calculating the area under the receiver operating characteristic curve and a Cox proportional-hazards regression model. A total of 254 patients with a median follow-up of 78 months were included in the study. LRE occurred in 28 patients (11%) during follow-up. In both patients with hepatitis B virus and hepatitis C virus (HCV), pSWE showed significant correlations with noninvasive tests and TE, and median pSWE and TE values were significantly different between patients with LREs and patients without LREs (both P  < 0.0001). In patients with HCV, the area under the receiver operating characteristic curve for pSWE and TE to predict LREs were comparable: 0.859 (95% confidence interval [CI], 0.747-0.969) and 0.852 (95% CI, 0.737-0.967) ( P  = 0.93). In Cox regression analysis, pSWE independently predicted LREs in all patients with HCV (hazard ratio, 17.9; 95% CI, 5.21-61-17; P  < 0.0001) and those who later received direct-acting antiviral therapy (hazard ratio, 17.11; 95% CI, 3.88-75.55; P  = 0.0002). Conclusion: Our study shows good comparability between pSWE and TE. pSWE is a promising tool for the prediction of LREs in patients with viral hepatitis, particularly those with chronic HCV. Further studies are needed to confirm our data and assess their prognostic value in other liver diseases., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

Background & Aims: Curing hepatitis C virus (HCV) infection reduces the risk of hepatocellular carcinoma (HCC) development, yet HCC occurs despite sustained virologic response (SVR) in 2%-8% of cirrhotic patients. Sphingolipids (SLs) have been identified as new biomarkers of chronic liver disease and HCC. The aim of this study was to evaluate serum SLs as diagnostic HCC biomarkers in patients with HCV-associated cirrhosis at SVR12., Methods: From 2014 to 2016, 166 patients with HCV-cirrhosis and SVR were recruited and SL profiles were measured at baseline and 12 weeks after completion of direct-acting antiviral (DAA) therapy. All patients received HCC surveillance in line with current guideline recommendations. Minimum follow-up period comprised 6 months., Results: Our study included 130 (78%) patients without history of HCC, 25 (15%) with history of HCC prior DAA therapy and 11 (7%) patients with de novo HCC after FU12. In those with upcoming de novo HCC serum C24DHC (P = 0.006), C24:1DHC (P = 0.048) and C16Cer (P = 0.011) were significantly upregulated at FU12, but not AFP (P = 0.138). Contemporaneous ultrasound did not visualize HCC, at this time. C16Cer stayed sole independent predictor with high diagnostic accuracy of AFP-positive (AUC = 0.741) and -negative (AUC = 0.766) HCC development. Serum SL parameters decreased from baseline to SVR12., Conclusions: C24DHC, C24:1DHC and especially C16Cer were superior to AFP in early detection of AFP-positive and -negative de novo HCC development. We observed significant SL profile changes upon SVR. SLs may play a role in non-invasive HCC surveillance and hepatocarcinogenesis., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Programmed cell death protein-1-targeted immunotherapy has shown promising results in phase II studies of hepatocellular carcinoma., Aim: To evaluate safety and efficacy of nivolumab and pembrolizumab in an international, multicentre, real-world cohort of patients with advanced hepatocellular carcinoma., Methods: Sixty-five patients treated with nivolumab (n = 34) or pembrolizumab (n = 31) between July 10, 2015 and December 31, 2018 (data cut-off) across six centres in Austria and Germany were retrospectively analysed., Results: Child-Pugh class A/B/C was 32 (49%)/28 (43%)/5 (8%). Immunotherapy was used as systemic first-/second-/third-/fourth-line treatment in 9 (14%)/27 (42%)/26 (40%)/3 (5%) patients. Fifty-four patients had at least one follow-up imaging and were, therefore, available for radiological response assessment. The overall response and disease control rates were 12% and 49% respectively. Of 52 evaluable patients, four (8%) had hyperprogressive disease. Median time to progression was 5.5 (95% CI, 3.5-7.4) months, median progression-free survival was 4.6 (95% CI, 3.0-6.2) months, and median overall survival was 11.0 (95% CI, 8.2-13.8) months. Most common adverse events were infections (n = 7), rash (n = 6), pruritus (n = 3), fatigue (n = 3), diarrhoea (n = 3) and hepatitis (n = 3). Efficacy and safety results were comparable between Child-Pugh A and B patients; however, median overall survival (OS) was shorter in Child-Pugh B patients (16.7 vs 8.6 months; P = 0.065). There was no difference in terms of efficacy and adverse events between patients who received immunotherapy as first-/second-line and third-/fourth-line respectively., Conclusions: Programmed cell death protein-1-targeted immunotherapy with nivolumab or pembrolizumab showed promising efficacy and safety in patients with advanced hepatocellular carcinoma, including subjects with Child-Pugh stage B and patients with intensive pretreatment., (© 2019 The Authors. Alimentary Pharmacology & Therapeutics Published by John Wiley & Sons Ltd.)

Background & Aims: Diverging trends of cholangiocarcinoma (CCA) incidence in different countries warrant further subtype-specific characterization. In this study, we aimed to determine current epidemiologic trends of CCA in Germany and evaluated impact of misclassification of perihilar CCA (pCCA) as intrahepatic CCA (iCCA)., Methods: Subtype-specific incidence was assessed based on data of approximately 40 million German citizens from 2003 to 2014, and mortality data of entire Germany were assessed from 1998 to 2015., Results: Reclassification of pCCA to extrahepatic CCA (eCCA) led to an enhancement of an increasing average annual percentage change (AAPC) for iCCA in men (3.8 to 4.8) and women (3.3 to 4.8). Likewise, a stable or slightly decreasing trend in extrahepatic CCA was strengthened in women (AAPC: -0.2 to -0.9) and men (1 to 0.5). pCCA accounted for 13% of biliary tract tumours (iCCA: 46%, distal CCA: 41%). In line with incidence trends, mortality of iCCA in Germany increased for women (AAPC 7.8) and men (6.5), while it was stable for eCCA (women: -0.6, men: 2.1)., Conclusion: Incidence of iCCA in Germany is increasing while it is stable for eCCA. Misclassification of pCCA as iCCA is present, but clearly declining., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Nivolumab is the first checkpoint-inhibitor approved for the treatment of advanced HCC patients. Real-life experience data of nivolumab treatment in HCC patients, especially those with advanced liver disease, is scarce., Materials and Methods: All patients with confirmed advanced HCC and nivolumab treatment from three large German centers were retrospectively analyzed. Clinical parameters and outcome were assessed., Results: A total of 34 patients were included. At the time of treatment initiation 5 patients (14.7%) were classified as stage BCLC B and 29 (85.3%) BCLC C, respectively. 25 (73.5) patients had received prior sorafenib treatment. All patients presented with cirrhosis, namely Child-Pugh stages A (56%) or B (41%), respectively. At time of patient's assessment, 20 out of 34 (58.8%) patients had died. Grade 3 toxicities occurred in two patients (5.9%). Best overall responses were partial response in four patients (11.8%) and stable disease in eight patients (23.5%). The median overall survival of the whole cohort was 7.5 weeks (range 0-46). Child-Pugh B stage disease at treatment start was significantly associated with poor outcome., Discussion: Nivolumab treatment seems safe and clinical efficacious. Patients with advanced liver disease require further prospective evaluation due to probable limited efficacy of nivolumab.